The present invention provides a novel process for preparing intermediates for known compounds. More particularly, the present invention provides an improved means for stereoselectively reducing known bicyclic lactone prostaglandin precursors in the preparation of prostaglandins. This reduction is undertaken using a borohydride salt and a trivalent lanthanide salt.
The prostaglandins are a family of compounds which are derivatives of prostanoic acid. (See, e.g., Bergstrom, et al., Pharmacol. Rev. 20: 1 (1968), and references cited therein.) A trivial system of nomenclature has been devised for this class of compounds, see, N. A. Nelson, Journal of Medicinal Chemistry, 17: 911 (1974). This system of nomenclature is used below.
The prostaglandins are known to be useful for a wide variety of pharmaceutical purposes including decreasing blood pressure, stimulating smooth muscles, inhibiting gastric secretion and protecting gastric mucosa, controlling spasms and facilitating breathing in asthmatic conditions, decongesting nasal passages, decreasing blood platelet adhesion and inhibiting blood platelet aggregation and thrombus formation, and a variety of uses in the reproductive area including labor induction, abortion, cervical dilatation, estrus regulation, and menstrual regulation. For a recent discussion of prostaglandins which are currently being developed commercially, see N. A. Nelson, et al., Chemical and Engineering News, pp. 30-44 (Aug. 16, 1982).
Initially, the prostaglandins were isolated from natural materials. However, several routes for the total chemical synthesis of the prostaglandins are now known. See, e.g. E. J. Corey, et al., J. Am. Chem. Soc. 91: 5675 (1969); E. J. Corey, et al., J. Am. Chem. Soc. 92: 397 (1970); and U.S. Pat. No. 3,711,515. These and many other prostaglandin synthetic methods proceed through a bicyclic lactone intermediate such as that of the Formula I.
Most of the commercially important prostaglandins are of the "natural" configuration, i.e., the same stereochemical configuration as the prostaglandins produced in mammalian matabolism. In particular, the stereochemical configuration of the hydroxy group at the 15-position of many of the commercially important prostaglandins is natural (i.e., alpha).
Two such commercially important prostaglandins are PGF.sub.2 .alpha. (see U.S. Pat. No. 3,706,789), which is marketed by The Upjohn Company for estrous synchronization, and 11-deoxy-11,16,16-trimethyl-PGE.sub.2 (see U.S. Pat. No. 4,052,446), a proposed anti-ulcer drug of Hoffmann-LaRoche, Inc.
In certain of the synthetic schemes for the preparation of prostaglandins, intermediates such as that of the Formula I are prepared from the corresponding ketones such as that of the Formula II. While numerous means exist for the reduction of this ketone, many are not stereospecific, i.e., they result in a mixture of epimers wherein the hydroxy group is in the alpha or beta position.
A number of reagents stated to be effective for stereoselective reduction of the 15-position of prostaglandins have been described. Thus, diisobutylaluminum 2,6-di-t-butyl-4-methylphenoxide (DIBAL-BHT) has been described in Iguchi, et al., Bull. Chem. Soc. Japan, 54: 3033 (1981), and Iguchi, et al., J. Org. Chem., 44: 1363 (1979). Certain lithium aluminum hydride compounds have been disclosed for this purpose in U.S. Pat. No. 4,284,581 and Noyori, et al., J. Amer. Chem. Soc. 101: 5843 (1979); and Noyori, Pure Appl. Chem. 53: 2315 (1981). Lithium thexyl limonyl borohydride (formed by treatment of limonene with thexyl borane and t-BuLi) is utilized in Corey, et al., J. Amer. Chem. Soc. 94: 8616 (1972). Lithium methyldiisopinocamphenyl borohydide and lithium-t-butyl-diisopinocamphenyl borohydride are employed in Corey, et al., J. Amer. Chem. Soc. 93: 1491 (1971). German Offen. No. 2,257,162 discloses the use of sodium cyanodiisopinocamphenyl brohydride. U.S. Pat. No. 4,247,635 discloses the use of certain microbes for this reduction. Hutton, et al., Syn. Com. 9: 799 (1979 ) discloses the use of various reagents produced by treatment of 3-O-benzyl-monocyclohexanone glucose with 1.0 equiv. lithium aluminumhydride and 1.0 equiv. of a monohydroxylic compound such as ethanol, adamantyl alcohol, and adamantylmethyl alcohol. British Pat. No. 1,498,764 discloses the use of potassium trialkyl borohydrides.
However, while each of these reagents is effective for stereospecific reduction of particular prostaglandin intermediates, none is effective for all such compounds.
Moreover, many of these reagents are optically active, which means that their use is limited to optically active prostanoid enone substrates. Further, none of these reagents is effective for the stereoselective reduction of a prostaglandin intermediate such as that of the Formula III. In addition, the reagents noted above are quite expensive and produce product mixtures from which the product can be isolated only with some difficulty. The only exception is DIBAL/BHT, which, as noted below, is not effective for stereoselective reduction of a compound of the Formula III.